Throughout this application, various references are referred to within parentheses. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
xcex1-Adrenergic receptors (Lomasney, J. W. et al., Biochim. Biophy. Acta 1991, 1095, 127) are cell membrane proteins located in both the peripheral and central nervous systems. They belong to a diverse family of structurally related receptors which contain seven putative transmembrane helices and couple to intracellular guanine nucleotide binding proteins (G-proteins). These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and apraclonidine (for glaucoma). xcex1-Adrenergic drugs can be divided into two distinct classes: agonists (like clonidine and naphazoline) which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (like phenoxybenzamine and prazosin) which act to block the effects of norepinephrine. However, many of these drugs, though effective, also produce undesirable side effects. For example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects.
Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptors xcex11 and xcex12 existed. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptorsxe2x80x94xcex11a, xcex11b, xcex11c, xcex12a, xcex12b and xcex12c (Bylund, D. B., FASEB J. 1992, 6, 832). In addition, current xcex12-adrenergic drugs are not selective for any particular xcex12-adrenergic receptor subtype. This lack of selectivity likely contributes to the untoward side effects of these drugs.
xcex12 receptors are located both presynaptically at nerve terminals and postsynaptically as in vascular smooth muscles, platelets, pancreatic xcex2-cells, and fat cells. Activation of the presynaptic receptors inhibit the release of norepinephrine by a negative feedback mechanism. Blockade of these receptors would therefore increase the release of norepinephrine.
It is believed that xcex12 receptors can modulate pain. Indeed, the effects of xcex12 agonists on analgesia, anesthesia and sedation have been well documented (Pertovaara, A., Progress in Neurobiology, 1993, 40, 691). For example, systemic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proves effective in producing analgesia. Another agonist, medetomidine, which has better xcex12/xcex11 selectivity and is more potent at xcex12 receptors than clonidine, has been shown in humans to be effective for ischemic pain even though the doses were high enough to produce sedation and considerable decrease in blood pressure.
However, in anesthetic practice, the sedative effect of xcex12 agonists is regarded as a good component of premedication.
Another beneficial effect of xcex12 agonists is their ability to potentiate the anesthetic action and hence to reduce the anesthetic requirements of other agents during surgery (Ghingnone, M. et al., Anesthesiology 1986, 64, 36).
Other potential uses of xcex12 agonists include lowering intraocular pressure, treating hypertension, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion (Cossement, E. et al., U.S. Pat. No. 4,923,865, 1990).
This invention is directed to imidazole and imidazoline compounds which are selective agonists for human xcex12 receptors. This invention is also related to the use of these compounds for treating disorders involving inhibition or lack of activation of xcex12 adrenergic receptors such as hypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion.
This invention is directed to imidazole and imidazoline compounds which are selective agonists for human xcex12 receptors. This invention is also related to the use of these compounds for treating disorders involving inhibition or lack of activation of a adrenergic receptors such as hypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
The present invention provides a compound having the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)3OH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R3 is independently H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2(CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound having the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; COR2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein q is each independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described herein and a pharmaceutically acceptable carrier.
The present invention further provides a method for treating an xcex12 adrenergic receptor associated disorder in a subject, which comprises administering to the subject an amount of a compound effective to treat the disorder, wherein the compound has the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4; polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH1)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R2 is independently H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; COR4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2(CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention additionally provides a method for treating an xcex12 adrenergic receptor associated disorder in a subject, which comprises administering to the subject an amount of a compound effective to treat the disorder, wherein the compound has the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein q is each independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for treating pain in a subject, which comprises administering to the subject an amount of a compound effective to treat the subject""s pain, wherein the compound has the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R3 is independently H; straight chained or branched C1-C4 alkyl; C1-C4, monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2(CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; (CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention provides a method for treating pain in a subject, which comprises administering to the subject an amount of a compound effective to treat the subject""s pain, wherein the compound has the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein q is each independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention is directed to compounds having the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NCO, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R3 is independently H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4; monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2(CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to compounds having the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein a is each independently C, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
Furthermore, the compounds of the present invention are preferably at least 80% pure, more preferably at least 90% pure, and most preferably at least 95% pure. The invention further provides for the (+) or (xe2x88x92) enantiomer of any of the compounds described herein such as a cis isomer or trans isomer.
The compounds of the present invention may be present as enantiomers, disteriomers or isomers, or as a racemic mixture.
The present invention also includes tautomeric forms of compounds I; e.g., when X is N and R2 on the adjacent carbon atom is xe2x80x94OH, R2 may tautomerize with X to form a ketone at R2.
The present invention also encompasses compounds wherein two R3s on different carbon atoms form a bridging methylene or ethylene.
In an embodiment of the present invention Y is CR3R5, and m+n is 3. In a further embodiment of the present invention Y is CR3R5 and m+n is 2.
In a further embodiment of the present invention Y is NR6. In another embodiment of the present invention X is N.
In an additional embodiment of the present invention two of Z1, Z2 and Z3 are CR2 and the other is N.
In an embodiment of the present invention p is at least 1 and at least one R3 is methyl. In a further embodiment of the present invention p is at least 1, at least one R3 is methyl and X is N.
In another embodiment of the present invention at least one R2 is methyl. In a further embodiment of the present invention R2 is methyl and X is N.
In yet another embodiment of the present invention at least one R2 is bromo. In a further embodiment of the present invention at least one R, is bromo and X is N.
In an additional embodiment of the present invention at least one R2 is methyl or phenyl. In yet another embodiment of the present invention R1 is C1-C3 alkyl, C1-C3 alkoxy, or xe2x80x94OH.
In an embodiment of the present invention the compound has the structure: 
In a further embodiment of the present invention the compound has the structure: 
In an additional embodiment of the present invention the compound has the structure: 
In a further embodiment of the present invention the compound has the structure: 
In an embodiment of the present invention the compound has the structure: 
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described herein and a pharmaceutically acceptable carrier. In the present invention a xe2x80x9ctherapeutically effective amountxe2x80x9d is any amount of a compound which, when administered to a subject suffering from a disorder against which the compound is effective, causes reduction, remission or regression of the disorder. In one embodiment, the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day, and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention, the xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
The invention includes the pharmaceutically acceptable salts and complexes of all the compounds described herein. The salts include but are not limited to the following acids and bases. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. Examples of suitable organic acids include but are not limited to acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid, citric acid and mandelic acid. Examples of suitable inorganic bases include, but are not limited to, ammonia, hydroxyethylamine and hydrazine. Examples of suitable organic bases include, but are not limited to, methylamine, ethylamine, trimethy amine, trethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. The invention further provides for the hydrates and polymorphs of all of the compounds described herein.
In one preferred embodiment, the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is in the form of a powder of tablet. In a further embodiment, the pharmaceutical carrier is a gel and the pharmaceutical composition is in the form of a suppository or cream. In a further embodiment, the compound may be formulated as part of a pharmaceutically acceptable transdermal patch.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for examples, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubillzers, emilsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant, which are useful for intranasal administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized for intramuscular, intrathecal, intratracheal, epidural, intraperitoneal or subcutaneous injections. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes and coatings.
The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders, and liquid forms such as solutions, syrups, elixirs and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Examples of suitable pharmaceutical carriers include any of the standard pharmaceutically accepted carriers known to those of ordinary skill in the art. Examples of such pharmaceutical carriers include, but are not limited to, phosphate buffered saline solution, water, emulsions such as oil/water emulsions or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules. A suitable pharmaceutically acceptable carrier may be selected taking into account the chosen mode of administration.
Besides containing an effective amount of the compounds described herein the pharmaceutical compositions may also include suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
The resulting pharmaceutical compositions may be liquids or lyophilized or otherwise dried formulations. Examples of suitable diluents include, but are not limited to, Tris-HCL, Tris-acetate and Tris-phosphate. The diluents employed may vary in their buffer content, pH and/or ionic strength. Examples of representative additives which may be used in the present invention include, but are not limited to, albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., Thimerosal, benzyalcohol), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparation of polymeric compounds such as polylactic acid, polyglycolic acid, polyvinyl pyrrolidone, etc. or into liposomes, microemulsions, micelles, unilamellar or multimellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compounds.
Examples of optional ingredients which may be included in the pharmaceutical compositions of the present invention include antioxidants, e.g., ascorbic acid; low molecular weight (less than about ten residues) polypeptides, i.e., polyarginine or tripeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; amino acids, such as glycine, glutamine acid, aspartic acid, or arginine; chelating agents such as EDTA; and sugar alcohols such as mannitol or sorbitol.
The choice of composition will depend on the physical and chemical properties of the compounds. Controlled or sustained release compositions include formulation of lipophilic depots (e.g., fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g., poloxamers or poloxamines) and compounds coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors. Other embodiments of the compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary nasal and oral.
Suitable topical formulations include gels, creams, solutions, emulsions, carbohydrate polymers, biodegradable matrices thereof; vapors, mists, a aerosols, or other inhalants. The compounds of the present invention may be encapsulated in a wafer, wax, film or solid carrier, including chewing gums. Permeation enhancers to aid in transport to movement across the epithelial layer are also known in the art and include, but are not limited to, dimethyl sulfoxide and glycols.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated, including subject age, weight, gender, diet, and time of administration, will result in a need to adjust dosages. Administration of the compound may be effected continuously or intermittently. One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating xcex12-mediated disorders, in particular the disorders described herein.
The present invention also provides a method for treating an xcex12 adrenergic receptor associated disorder in a subject, which comprises administering to the subject an amount of a compound effective to treat the disorder, wherein the compound has the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R3 is independently H; straight chained or branched C1-C4alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2 (CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The subject invention further provides a method for treating an xcex12 adrenergic receptor associated disorder in a subject, which comprises administering to the subject an amount of a compound effective to treat the disorder, wherein the compound has the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein q is each independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
Examples of xcex12 adrenergic receptor associated disorders which may be treated in accordance with the subject invention include, but are not limited to, hypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion.
In a specific embodiment of the present invention the xcex12 adrenergic receptor associated disorder is migraine headache, hypertension or glaucoma.
The present invention also provides a method for treating pain in a subject, which comprises administering to the subject an amount of a compound effective to treat the subject""s pain, wherein the compound has the structure: 
wherein X is CR7; N; or N+Oxe2x88x92;
wherein Y is O; CO; S; CR3R5; or NR6;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R3 is independently H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94(CH2)qOH; xe2x80x94OH; xe2x95x90Nxe2x80x94OR4; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl;
wherein each R5 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl, or C1-C4 polyfluoroalkyl;
wherein R6 is H; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94CH2CH2(CH2)qOH; COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R7 is independently H; xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH2)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein m and n are each independently 0, 1, 2 or 3, provided that m+n is 2 or 3;
wherein each p is independently 0, 1 or 2; and
wherein each q is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for treating pain in a subject, which comprises administering to the subject an amount of a compound effective to treat the subject""s pain, wherein the compound has the structure: 
wherein each of Z1, Z2 and Z3 is N or CR2, with the proviso that either one of Z1, Z2 or Z3 is N and the others of Z1, Z2 or Z3 are CR2, or both Z1 and Z3 are N and Z2 is CR2;
wherein R1 is H; F; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy, xe2x80x94OH; or xe2x80x94(CH2)qOH;
wherein each R2 is independently H; F; Cl; Br; I; xe2x80x94NO2, xe2x80x94CN; straight chained or branched C1-C4 alkyl; C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; straight chained or branched C1-C4 alkoxy; xe2x80x94OH; xe2x80x94(CH)qOH; xe2x80x94COR4; CO2R4; CONHR4; phenyl; or benzyl;
wherein each R4 is independently H; straight chained or branched C1-C4 alkyl, C1-C4 monofluoroalkyl or C1-C4 polyfluoroalkyl; or phenyl; and
wherein q is each independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.